A major emphasis of this project has been to define the relationship of exogenous hormones to subsequent cancer risk. Our most recent analyses have assesed the relationships of menopausal hormones to gynecologic cancer cancer risk using data from our large, prospective cohort studies. Using data from the NIH-AARP Diet and Health Cohort Study, we have clarified some unresolved issues regarding ovarian cancer risk in women who use menopausal hormone therapy. Increased ovarian cancer risks among women who used unopposed estrogen therapy for 10 or more years provide further evidence to support the hypothesis that increased estrogen levels after menopause can influence the development of ovarian cancer. In addition, this study provided some of the first strong evidence that specifically links estrogen plus progestin use to increased ovarian cancer risk in women with intact uteri. These results reiterate the value of long-term follow-up of existing cohorts to elucidate increased risks of rare outcomes, such as ovarian cancer, among women who exposed to menopausal hormone therapy. Ongoing analyses in this cohort are exploring the relationships between specific patterns of hormone therapy use and other cancer sites, such as endometrial cancer.We have also had an interest in effects of other hormonal exposures, including ovulation stimulating drugs used to treat infertility. A retrospective cohort study was also conducted which allowed an assessment of effects on cancer risk of different causes of infertility and associated therapies. This study involved detailed abstraction of medical records of patients diagnosed as long ago as the 1960's and administration of questionnaires to obtained updated health information. A strength of the study was the detailed information collected on causes of infertility. Analyses showed that type of infertility (primary vs. secondary) was a more important predictor of cancer risk than specific causes of infertility. However, patients with endometriosis were at an especially high risk of developing ovarian cancer. In general, the study provided reassuring results regarding use of ovulation-inducing agents, showing no major increases in cancer risk relating to use of either clomiphene citrate or human menopausal gonadotropins. There were, however, slight increases in risk of both breast and ovarian cancers among the subjects followed for the longest periods of time (15 or 20+ years), supporting the need for additional monitoring of long-term effects of these agents. Certain medical devices have also been of interest, including the long-term safetly of silicone breast implants. Effects on breast cancer risk has been of concern, given that breast implants can interfere with the mammographic visualization of lesions. However, in a large retrospective study that we conducted, we found no evidence for an alteration in breast cancer risk. These patients also generally did not experience alterations in other cancer sites, although elevations were observed in the risk of lung and brain cancers, the explanation for which remains unclear. In a mortality analysis, implant patients had signficantly elevated risks of death from suicide, but other causes of death were similar to the general population. The patients in this study are continuing to be followed for future mortal events, of importance given the aging nature of the study population. We also recently assessed effects on various connective tissue diseases. In general, the results were fairly reassuring, although this investigation did highlight the complexities of evaluating the associations, given the rarity of most individual diseases, and a variety of diagnostic and reporting difficulties. Recent cohort studies demonstrated reduced breast cancer risks among women with a history of fractures or low bone mineral density.